目的:巨噬细胞中胆固醇的过度积累是动脉粥样硬化斑块形成的关键步骤。我们在这里探索RA患者血清中的因素,以及它们与巨噬细胞的胆固醇负荷能力(CLC)相互作用并影响其的机制。
方法:在104例RA患者的横断面观察队列中,CLC测量为在与患者血清孵育后的人THP-1衍生的巨噬细胞中的细胞内胆固醇含量。低密度脂蛋白(LDL)氧化是根据含apoB100的颗粒(oxPL-apoB100)上的氧化磷脂来测量的。抗氧化LDL抗体(抗oxLDL),还定量了前蛋白转化酶枯草杆菌蛋白酶/Kexin9型(PCSK9)和高敏CRP。所有分析调整了动脉粥样硬化性心血管疾病(ASCVD)风险评分,肥胖,总LDL,他汀类药物的使用,诊断时的年龄,和抗oxLDLIgM。
结果:OxPL-apoB100,抗oxLDLIgG和PCSK9与CLC呈正相关(均P<0.020)。OxPL-apoB100仅在双重RF和ACPA阳性患者中直接影响CLC[未标准化b(95%bootstrapCI)=2.08(0.38,3.79)]。oxPL-apoB100通过抗oxLDLIgG对CLC的间接作用增加,随着CRP水平[温和调解指数=0.55(0.05-1.17)]。CRP还通过上调PCSK9来调节oxPL-apoB100对CLC的另一种间接作用,但仅在双血清阳性患者中[条件间接作用=0.64(0.13-1.30)]。
结论:氧化LDL可直接影响血清双阳性RA患者的CLC。另外两个独立的途径-通过抗oxLDLIgG和PCSK9-可能介导oxPL-apoB100对CLC的影响,取决于CRP和血清阳性状态。如果经过外部验证,这些发现可能对预防心血管风险有临床意义.
Excessive cholesterol accumulation in macrophages is the pivotal step underlying atherosclerotic plaque formation. We here explore factors in the serum of patients with RA, and mechanisms through which they interact with and influence cholesterol loading capacity (CLC) of macrophages.
In a cross-sectional observational cohort of 104 patients with RA, CLC was measured as intracellular cholesterol content in human THP-1-derived macrophages after incubation with patient serum. Low-density lipoprotein (LDL) oxidation was measured in terms of oxidized phospholipids on apoB100-containing particles (oxPL-apoB100). Antibodies against oxidized LDL (anti-oxLDL), proprotein convertase subtilisin/Kexin type-9 (PCSK9) and high-sensitivity CRP were also quantified. All analyses adjusted for atherosclerotic cardiovascular disease (ASCVD) risk score, obesity, total LDL, statin use, age at diagnosis, and anti-oxLDL IgM.
OxPL-apoB100, anti-oxLDL IgG and PCSK9 were positively associated with CLC (all P < 0.020). OxPL-apoB100 directly influenced CLC only in dual RF- and ACPA-positive patients [unstandardized b (95% bootstrap CI)=2.08 (0.38, 3.79)]. An indirect effect of oxPL-apoB100 on CLC through anti-oxLDL IgG increased, along with level of CRP [index of moderated mediation = 0.55 (0.05-1.17)]. CRP also moderated yet another indirect effect of oxPL-apoB100 on CLC through upregulation of PCSK9, but only among dual-seropositive patients [conditional indirect effect = 0.64 (0.13-1.30)].
Oxidized LDL can directly influence CLC in dual-seropositive RA patients. Two additional and independent pathways-via anti-oxLDL IgG and PCSK9-may mediate the effects of oxPL-apoB100 on CLC, depending on CRP and seropositivity status. If externally validated, these findings may have clinical implications for cardiovascular risk prevention.